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PubMed1993

Patch clamp studies on the kinetics and selectivity of N-methyl-D-aspartate receptor antagonism by memantine (1-amino-3,5-dimethyladamantan).

Memantine (1-amino-3,5-dimethyladamantan) was tested as an antagonist of N-methyl-D-aspartate (NMDA) receptors on cultured superior collicular and hippocampal neurones using the patch clamp technique and its actions were compared to those of Mg2+ ions, ketamine, dextrorphan, dextromethorphan, phencyclidine and dizocilpine (MK-801). Memantine (2-33 microM) concentration-dependently antagonized responses to NMDA 100 microM with an IC50 of 2.92 +/- 0.05 microM. In contrast, current responses to (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (L-AMPA 50-100 microM) and gamma-amino butyric acid (GABA 10 microM) were unaffected by Memantine 8 microM. Memantine 8 microM caused a non-parallel shift of the NMDA concentration-response curve to the right in a manner indicative of uncompetitive open channel block. The effects of memantine were similar to ketamine in that both antagonists were weakly use- and strongly voltage-dependent. In contrast, MK-801, phencyclidine and dextrorphan showed much slower kinetics that was reflected in their marked use- and weaker voltage-dependency. The antagonistic effects of memantine were not reversed by increasing concentrations of glycine (0.1-100 microM) ruling out the possibility of an interaction of memantine with the strychnine-insensitive glycine modulatory site associated with the NMDA receptor-channel complex. Memantine (1-100 microM) also selectively antagonized responses to NMDA (40 microM) in the cortical wedge preparation with IC50 of 12.9 +/- 1.5 microM.

Animals↗
PubMed1983

Opiate regulation of maternal behavior in the rat.

The effects of the opiate agonist morphine, the opiate antagonist naloxone and the weak opiate nonanalgesic dextrorphan on the expression of maternal behavior were investigated in a series of three experiments. In the first experiment treatment of rats with morphine (5 mg/kg, subcutaneously) after ovariectomy and hysterectomy on day 17 of gestation resulted in a disruption in the onset and quality of maternal responsiveness in the homecage and in a T-maze test. The duration of morphine's acute disruptive action was 2-4 hours. In the second experiment concurrent treatment of morphine-injected rats with naloxone prevented the disruptive effects of morphine in both the homecage and T-maze tests. The effects of morphine did not appear to result from a severe alteration in activity levels as measured in an open-field test, although morphine did increase activity slightly by the fifth day of treatment. In the third experiment treatment of rats after ovariectomy plus hysterectomy on day 17 of gestation with dextrorphan failed to disrupt maternal behavior. These results indicate that morphine disrupts maternal behavior through an opiate receptor mechanism, and suggests to us that endogenous opiates may mediate the expression of maternal behavior under certain physiological conditions.

Animals↗
PubMed1985

Behavioral response to apomorphine and its interaction with opiates in domestic pigeons.

Domestic pigeons received peripheral injections of saline or the dopamine agonist apomorphine (AM) at doses of 0.025, 0.05, 0.1, 0.25, 0.5 or 1 mg and their behavior was studied for 30 min after these treatments. Given at a dose of 0.025 mg, AM decreased pecking, whereas doses ranging from 0.1 to 1 mg strongly stimulated this behavior. The frequency of headshaking was enhanced by the administration of each dose of AM; at the 3 higher doses, the drug also attenuated the frequency of preening. In another experiment, AM was administered 40 min after the injection of either naloxone (0.5, 1 or 4 mg), the opiate agonist levorphanol (0.25, 0.5 or 1 mg) or its dextroisomer, dextrorphan (0.25, 0.5 or 1 mg), while the birds were observed as before. No interaction between AM and either naloxone or dextrorphan was detected. By contrast, injection of each dose of levorphanol attenuated preening, and completely antagonized the stimulating effect of AM treatment on headshaking. At a dose of 1 mg, levorphanol also slightly decreased the frequency and increased the latency of occurrence of pecking. It is concluded that in pigeons, opiates modulate the behavioral response to apomorphine in a complex fashion.

Animals↗
PubMed1989

Genetically determined oxidation polymorphism and drug hepatotoxicity. Study of 51 patients.

The influence of genetically determined oxidation polymorphism on drug hepatotoxicity has been poorly investigated and results are controversial. We studied drug oxidation capacity in 51 patients with hepatitis caused mainly by drugs undergoing oxidative metabolism, using dextromethorphan, a test compound recently proposed as a substitute for debrisoquine. Phenotyping was performed using the metabolic ratio (MR) calculated as MR = 0-10 h urinary output of dextromethorphan/0-10 h urinary output of dextrorphan (the main oxidative metabolite), after oral administration of 40 mg dextromethorphan hydrobromide. Dextromethorphan oxidation capacity was similar in patients and in 103 control subjects as judged by: (a) the prevalence of each phenotype (5.9% versus 3.9% for the poor metabolizer phenotype and 94.1% versus 96.1% for the extensive metabolizer phenotype; (b) the frequency distribution histograms of log metabolic ratio; (c) the mean values of dextromethorphan and dextrorphan urinary outputs and of log metabolic ratio for each phenotype. These results show that hepatotoxicity of several drugs, including amineptine, amodiaquine and Plethoryl, is related neither to an impairment in dextromethorphan oxidation capacity nor to an unusually high capacity to oxidize this drug.

Adolescent↗
PubMed1992

Pretreatment with NMDA antagonists limits release of excitatory amino acids following traumatic brain injury.

After central nervous system (CNS) trauma, there are marked elevations in the extracellular levels of excitatory amino acids (EAA), which are believed to contribute to delayed tissue damage. Administration of N-methyl-D-aspartate (NMDA) receptor antagonists reduces injury severity after brain or spinal cord trauma, presumably by blocking the postsynaptic NMDA receptor. In the present studies, levels of extracellular amino acids were monitored by microdialysis during, and after, a moderately severe fluid-percussion brain injury to rats. Pretreatment (15 min prior to injury) with the non-competitive NMDA antagonist dextrorphan or the competitive NMDA antagonist CGS 19755 significantly attenuated the post-traumatic increase in extracellular glutamate. Pretreatment with dextrorphan attenuated the post-traumatic increase in extracellular levels of aspartate; although these differences did not reach significance when examined as absolute values, they were significant when analyzed as percent increase over pre-trauma baseline levels. These results are consistent with recent experiments and suggest that NMDA antagonists may limit the release of glutamate and aspartate after trauma through a presynaptic mechanism.

Amino Acids↗
PubMed1999

Influence of pretreatment with immunosuppressants on O-demethylation of dextromethorphan in isolated perfused rat liver.

Changes in the immune system induced by exogenous or endogenous factors may be accompanied with modifications of the activity of the drug metabolising enzymes in the liver. Some immunostimulatory agents are known to suppress the oxidative metabolism mediated by cytochromes P450. Possible effects of substances which suppress the immune responses of the organism have not been fully understood yet. The present study was undertaken to investigate the influence of immunosuppressants cyclophosphamide and dexamethasone on the CYP2D 1-dependent metabolism of dextromethorphan (DEM) in the isolated perfused liver from male rat donors (Wistar albino, 250-310 g). Recirculatory perfusion system was used with Williams' medium E (Sigma Chemicals Co.) as a perfusion medium (120 mL). DEM was administered as a 1 mg bolus into the perfusion solution at the start of each experiment after 20 min preperfusion. Samples of perfusate for HPLC determination of DEM and its O-demethylated metabolite dextrorphan (DOR) were taken at 15 min intervals for 120 min. The results have shown a rapid conversion of DEM to DOR in the isolated rat liver preparations. Pharmacokinetic parameters in the livers from intact rats were as follows: t1/2 DEM = 19.1+/-4.10 min, k(m) = 0.035+/-0.008 min(-1), Cl(m) = 4.21+/-0.97 mL x min(-1), AUC(DOR) = 2160+/-201 microg x min x L(-1). Pretreatment of rats with dexamethasone (4 mg/kg/day, iv, x 3 days) led to a significant increase in the concentration of dextrorphan in the recirculating solution, but it did not substantially change the kinetic constants of DOR formation (km = 0.036+/-0.004 min(-1), Cl(m) = 4.27+/-0.43 mL x min(-1)). Cyclophosphamide (100 mg/kg, ip, 1 dose on day 5 before perfusion) induced nearly twofold increase in the DOR concentrations in perfusate and thus highly significant (p < 0.01) changes of the kinetic parameters characterizing the increased rate of conversion of DEM to DOR (t1/2 DEM = 12.1+/-0.90 min, km = 0.055+/-0.004 min(-1), Cl(m) = 7.09+/-1.37 mL x min(-1), AUC(DOR) = 3602+/-154 microg x min x L(-1)). Considering that both cyclophosphamide and dexamethasone belong to the most widely used immunosuppressive drugs, their potential to promote the CYP2D-mediated metabolism might have a clinical impact in combined therapy of autoimmune or other diseases.

Alcohol Oxidoreductases↗
PubMed1989

Phenotypic differences in dextromethorphan metabolism.

Polymorphic differences in dextromethorphan metabolism were observed in three studies conducted in a total of 44 subjects (of Dutch origin) administered 60 mg dextromethorphan hydrobromide as an OROS tablet. Mean plasma dextromethorphan (DM) concentrations after a single dose and at steady state were 4-75 times higher in the poor metabolizers (PM) relative to the extensive metabolizers (EM). Following a single dose, the mean areas under the plasma concentration-time curve (AUC, 0-24 hr) of DM, total dextrorphan (DR), and total 3-hydroxymorphinan (HM) were 6.9-fold higher, 17.4-fold lower, and 11-fold lower, respectively, for the PM than for the EM. Correspondingly, steady-state AUC values were 52.8 times higher, 6.7 times lower, and 3.3 times lower for DM, total DR, and total HM, respectively, for the PM relative to the EM. Drug/metabolite ratios (DMR) for amounts excreted in the urine of DR and HM indicated polymorphism in O-demethylation of DM since DMR for PM was 352 and 338 times higher than that for EM for DR and HM, respectively. However, polymorphism in N-demethylation was not observed. Ratios of conjugated/free dextrorphan and 3-hydroxymorphinan excreted in the urine suggest also a lack of conjugative capacity in the PM, relative to the EM. The overall incidence of PM was 9.1% in this population.

Administration, Oral↗
PubMed1985

Polymorphic dextromethorphan metabolism: co-segregation of oxidative O-demethylation with debrisoquin hydroxylation.

Dextromethorphan hydrobromide, 25 mg po, was given to 268 unrelated Swiss subjects to study urinary drug and metabolite profiles. Rates of O-demethylation yielding the main metabolite dextrorphan were expressed by the urinary dextromethorphan/dextrorphan metabolic ratio. We found a bimodal distribution of this parameter in our population study, which indicates that there are two phenotypes for dextromethorphan O-demethylation. The antimode at a metabolic ratio of 0.3 separated the poor metabolizer (PM; n = 23; prevalence of 9%) from extensive metabolizer (EM) phenotypes. Urinary output of dextrorphan was less than 6% of the dose in all PMs and was 50% in the 245 EMs. Pedigree analysis of 14 family studies revealed an autosomal-recessive transmission of deficient dextromethorphan O-demethylation. In these families, 37 heterozygous genotypes could be identified; however, through use of the urinary drug and metabolite analysis it was not possible to identify the heterozygous genotypes within the EM phenotype group. Co-segregation of dextromethorphan O-demethylation with debrisoquin 4-hydroxylation was also studied. Complete concordance of the two phenotypic assignments was obtained, with a Spearman rank correlation coefficient of rs = 0.78 (n = 62; P less than 0.0001) for dextromethorphan and debrisoquin metabolic ratios. Presumably the two drug oxidation polymorphisms are under the same genetic control. Thus the innocuousness and ubiquitous availability of dextromethorphan render it attractive for worldwide pharmacogenetic investigations in man.

Administration, Oral↗
PubMed2001

Potent inhibition of CYP2D6 by haloperidol metabolites: stereoselective inhibition by reduced haloperidol.

AIMS: We evaluated the inhibitory effect of haloperidol and its metabolites on CYP2D6 activity in order to better understand the potential role of these metabolites in drug interactions involving haloperidol. METHODS: The inhibitory effects of haloperidol and five of its metabolites on dextrorphan formation from dextromethorphan, a marker probe of CYP2D6 activity, were measured in human liver microsomal preparations. Apparent kinetic parameters for enzyme inhibition were determined by nonlinear regression analysis of the data. RESULTS: Racemic reduced haloperidol and its metabolite, RHPTP competitively inhibited dextromethorphan O-demethylation with estimated Ki values (0.24 microM and 0.09 microM, respectively) that were substantially lower than that of haloperidol (0.89 microM). The inhibitory effect of S(-)-reduced haloperidol was more potent than the R(+)-enantiomer, with estimated Ki values of 0.11 microM and 1.1 microM, respectively. The pyridinium metabolite of haloperidol, HPP+ inhibited the enzyme activity noncompetitively with a Ki value of 0.79 microM. The N-dealkylated metabolites of haloperidol (FBPA and CPHP) had a diminished inhibitory potency. While FBPA showed no notable inhibitory effect on dextrorphan formation, CPHP showed moderate competitive inhibition with a Ki value of 20.9 microM. CONCLUSIONS: The principal metabolites of haloperidol inhibit CYP2D6, suggesting that they might contribute to the inhibitory effects of the drug. Reduced haloperidol seems to inhibit CYP2D6 activity in an enantioselective manner with the physiologically occurring S(-) enantiomer being more potent.

Binding, Competitive↗
PubMed1996

An isobolographic analysis of the effects of N-methyl-D-aspartate and NK1 tachykinin receptor antagonists on inflammatory hyperalgesia in the rat.

1. The interaction between N-methyl-D-aspartate (NMDA) and NK1 tachykinin receptors was analyzed isobolographically in rats with inflammatory hyperalgesia induced by intraplantar injection of complete Freund's adjuvant-saline emulsion (CFA, 100 micrograms Mycobacterium tuberculosis). 2. Thermal hyperalgesia of the inflamed paw, determined by paw withdrawal response to a heat stimulus, was dose-dependently attenuated by intrathecal administration of an NMDA receptor antagonist, dextrorphan (2.5-40 micrograms, ED50 = 7.2 micrograms), and two NK1 tachykinin receptor antagonists, WIN 51,708 (0.01-200 micrograms, ED50 = 10.4 micrograms) or CP-96,345 (5-200 micrograms, ED50 = 82.1 micrograms). There was no effect of these agents on the nociceptive threshold of the non-inflamed paw. CP-96,344, an enantiomer of CP-96,345 that is inactive as an NK1 tachykinin receptor antagonist, slightly attenuated hyperalgesia at a dose of 200 micrograms. 3. Combinations of dextrorphan and WIN 51,708 were administered at fixed ratios (10%:90%; 41%:59%; 90%:10%). Isobolographic analysis revealed that the ED50s obtained from the three combination ratios were not significantly different from those that were expected from a simple additive effect. 4. Thus, an additive interaction was demonstrated between NMDA and NK1 tachykinin receptor systems at the spinal level. These results suggest that both NMDA and NK1 tachykinin receptors are activated in response to peripheral inflammation, but that they may contribute independently to development of hyperalgesia.

Androstanes↗
PubMed1994

Effects of NMDA- and AMPA-receptor antagonists on different forms of epileptiform activity in rat temporal cortex slices.

Lowering extracellular magnesium induces different patterns of epileptiform activity in rat hippocampus and entorhinal cortex. Short recurrent epileptiform discharges in the hippocampus are stable over time, whereas seizure-like events (SLEs) in the entorhinal cortex, the subiculum, and the neighboring neocortex develop into late recurrent discharges which are not blocked by clinically employed antiepileptic drugs. We tested the sensitivity of the different epileptiform discharge patterns to N-methyl-D-aspartate (NMDA)- and non-NMDA-receptor antagonists. As NMDA-receptor antagonist we used dextrorphan, ketamine, and 2-aminophosphonovalerate (2APV); as alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA)-receptor antagonist we employed the quinoxaline derivative glutamate 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). The findings show that the different patterns of epileptiform activity, including the late recurrent discharges, are sensitive to all NMDA-receptor antagonists. However, when dextrorphan was employed to suppress seizure-like events, later recurrent discharges did not develop during the remaining time course of the experiment. CNQX reversibly suppressed recurrent discharges in the hippocampus and SLEs in the entorhinal cortex. However, late recurrent discharges become insensitive to CNQX, even at a high concentration of 60 microns. This finding suggests a prominent role for NMDA receptors in the generation of late recurrent discharges.

2-Amino-5-phosphonovalerate↗
PubMed2001

Evaluation of CYP2D6 oxidation of dextromethorphan and propafenone in a Chinese population with atrial fibrillation.

The objective of this study was to determine the percentage of patients with paroxysmal atrial fibrillation who were poor metabolizers of CYP2D6 in a Chinese population from Hong Kong and to assess the relationship between the dextromethorphan/dextrorphan ratio and the propafenone/5-hydroxypropafenone ratio or the steady-state propafenone concentration. Patients (n = 60) were recruited from the Arrhythmia Clinic at the University of Hong Kong and given dextromethorphan 30 mg. The dextromethorphan and dextrorphan concentrations in urine over the next 8 hours were used to determine metabolizer status. If the metabolic ratio was greater than 0.3, the patient was determined to be a poor metabolizer. In phase 2, patients (n = 38) were given propafenone 150 mg twice daily, and at steady state, the propafenone and 5-OH propafenone plasma concentrations were determined. It was found that 15% of the patients were poor metabolizers of dextromethorphan. There was a significant correlation between the metabolic ratios of dextromethorphan/dextrorphan and propafenone/5-OH propafenone (r = 0.49, p = 0.0019) and between the dextromethorphan/dextrorphan ratio and the concentration of propafenone (r = 0.32, p = 0.05). No correlations were found in the extensive or poor metabolizer subgroups. It was concluded that the percentage of poor metabolizers in atrial fibrillation patients from Hong Kong was much larger than in previous studies of Chinese patients who were not from Hong Kong. The ability to metabolize dextromethorphan to dextrorphan is related to the ability to metabolize propafenone to 5-hydroxypropafenone.

Anti-Arrhythmia Agents↗
PubMed1975

Saturable binding of dihydromorphine and naloxone to rat brain tissue in vitro.

The binding in vitro of an opiate agonist, 3H-dihydromorphine, was studied using a particulate fraction obtained from rat brain homogenates and compared with that of an opiate antagonist, 3H-naloxone. The binding of 3H-dihydromorphine may be separated into two components: one a saturable component and the other nonsaturable. The saturable binding may be calculated from the differences in binding observed in the absence and presence of high concentrations of levorphanol. The use of dextrorphan results in an artifactual separation of this component, although relative stereospecificity was observed for levorphanol and dextrorphan. There were marked regional differences in the distribution of saturable 3H-dihydromorphine binding in the brain. These were primarily due to the difference in the concentration of the saturable binding sites within various brain regions. It appeared that the saturable binding sites from various brain regions had similar affinities for dihydromorphine except for the binding site from cerebral cortex which had a higher affinity. In contrast, saturable binding sites for naloxone in various brain regions had different affinities for naloxone. It appears that naloxone has at least two types of saturable binding sites, one of which is not available to dihydromorphine. This is based on observations 1) that the total concentration of saturable binding sites for naloxone was greater than that for dihydromorphine in each brain region studied irrespective of the assay medium used and 2) that unlabeled dihydromorphine inhibited the 3H-naloxone binding in striatum but failed to alter it significantly in cerebellum, whereas unlabeled naloxone reduced 3H-naloxone binding significantly in both brain regions. The difference in concentrations of saturable binding sites for naloxone and dihydromorphine was relatively small in striatum but larger in cerebellum, indicating that the saturable binding sites in cerebellum are predominantly naloxone-specific, whereas those in striatum are capable of binding both naloxone and dihydromorphine. In cerebrospinal fluid or in simulated intracellular fluid, the apparent affinity for dihydromorphine was lower and that for naloxone was higher than in Tris-HCl buffer. It is concluded that naloxone binds to dihydromorphine binding site and to another site, which has a different affinity for naloxone and is not available to dihydromorphine. Studies in which opiate receptor binding was assayed in Tris-HCl buffer may need to be re-evaluated. Further, in studies where opiate binding in vitro is assessed following pharmacologic intervention, such binding should be estimated in a relevant physiological medium rather than in Tris-HCl buffer.

Animals↗
PubMed1991

MK-801 and related compounds in monkeys: discriminative stimulus effects and effects on a conditional discrimination.

MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10-imine maleate] and related compounds were studied in monkeys discriminating between 0.032 mg/kg of (+)-MK-801 and saline and in a separate group of monkeys responding under a multiple schedule of repeated acquisition and performance of conditional discriminations. In the drug discrimination study, small doses of (+)-MK-801 occasioned saline-lever responding whereas larger doses occasioned responding on the MK-801 lever. Dexoxadrol substituted completely (greater than or equal to 90%) for the MK-801 discriminative stimulus in all subjects whereas dextrorphan and phencyclidine (PCP) substituted in only two of three subjects. Neither ketamine, (+)-N-allylnormetazocine, dextromethorphan nor the competitive excitatory amino acid antagonist CGS 19755 [cis-4-phosphonomethyl-2-piperidine-carboxylic acid] substituted for MK-801 in any of the monkeys. PCP, dextrorphan, dextromethorphan, (+)- and (-)-MK-801 decreased rates of lever pressing and increased errors in both components of the multiple acquisition, performance schedule. For each compound errors were increased in the acquisition component with doses smaller than doses required to increase errors in the performance component. In both procedures (+)-MK-801 was 10 times more potent than (-)-MK-801, although qualitatively similar results were obtained with the two enantiomers. PCP-like drugs have many effects in common, including their effects on learning and performance; however, with regard to discriminative stimulus effects this does not appear to be a homogenous pharmacological class, suggesting that change in excitatory amino acid-mediated neurotransmission might not be the only mechanism by which MK-801 and related compounds exert behavioral effects in nonhuman primates.

Analgesics↗
PubMed1987

Myocardial opiate receptor activity is stereospecific, independent of muscarinic receptor antagonism, and may play a role in depressing cardiac function.

Earlier work has shown that morphine sulfate can produce a dose-related decrease in heart rate (HR) and cardiac output (CO) in isolated working rat hearts. This response is preventable with the use of the opiate receptor antagonist, naloxone hydrochloride. In this study, the stereospecificity of the opiate response was tested with the use of levorphanol tartrate and its d-isomer, dextrorphan, in our Langendorff rat heart model. The interaction of muscarinic receptor activity with the opiate response was tested by first adding bethanechol chloride to the perfusate in the presence and absence of atropine (5 X 10(-9) mmol/L). Our earlier studies with morphine sulfate were then repeated in the presence of the same concentration of atropine. At a concentration of 5 X 10(-6) mmol/L, levorphanol tartrate produced a significant decrease in CO (p less than 0.05), while a similar concentration of dextrorphan produced little change in either HR or CO. Bethanechol chloride, in a concentration of 3 X 10(-6) mmol/L, produced a significant decrease in HR and CO (p less than 0.05), which was prevented by atropine. When morphine sulfate was added to the standard perfusate (3 X 10(-4) mmol/L), HR and CO were significantly decreased (p less than 0.05). This change was not prevented by the addition of atropine. The opiate effect on myocardial function is mediated by a stereospecific opiate receptor, which acts independently of muscarinic receptor antagonism.

Animals↗
PubMed1987

Opioid analgesia at peripheral sites: a target for opioids released during stress and inflammation?

The peripheral analgesic effects of opiates were evaluated in a rat model of inflammation. The experimental design excluded a potential central nervous system site of action for the observed analgesia. After the injection of carrageenan (CARRA) in the plantar surface of both hind paws, an opiate was injected into one paw and saline was injected into the other paw. The inflamed paws injected with the mu-agonist, fentanyl (0.3 micrograms) or the kappa-agonist, ethylketocyclazocine (10 micrograms) were significantly less hyperalgesic (P less than 0.001 and P less than 0.01, respectively) than were the contralateral inflamed paws injected with saline. At these doses, fentanyl and ethylketocyclazocine were devoid of systemic effects. Another mu-agonist, levorphanol (20, 40, 80, or 160 micrograms) and dextrorphan (160 micrograms), its dextrorotatory isomer, were used next to evaluate opioid specificity. Levorphanol produced a dose-related blockade of CARRA-induced hyperalgesia (P less than 0.005). In contrast, 160 micrograms of dextrorphan was inactive. These results demonstrate that local administration of opiates into an inflamed paw produces a dose-related, stereospecific analgesia restricted to the injected area.

Analgesics, Opioid↗
PubMed1997

Efficacy of spinal NMDA receptor antagonism in formalin hyperalgesia and nerve injury evoked allodynia in the rat.

Neuropathic pain remains a significant clinical problem. Current understanding implicates the spinal cord dorsal horn N-methyl-d-aspartate (NMDA) receptor apparatus in its pathogenesis. Previous reports have described NMDA antagonist reduction of nerve injury-induced thermal hyperalgesia and formalin injection-related electrical activity. We examined a panel of spinally administered NMDA antagonists in two models: allodynia evoked by tight ligation of the fifth and sixth lumbar spinal nerves (a model of chronic nerve injury pain), and the formalin paw test (a model wherein pretreatment with drug may preempt the development of a pain state). A wide range of efficacies was observed. In the nerve injury model, order of efficacy (expressed as percent of maximum possible effect +/- S.E.), at the maximum dose not yielding motor impairment, was memantine (96 +/- 5%) = AP5 (91 +/- 7%) > dextrorphan (64 +/- 11%) = dextromethorphan (65 +/- 22%) > MK801 (34 +/- 8%) > ketamine (18 +/- 6%). For the formalin test, the order of efficacy was AP5 (86 +/- 9%) > memantine (74 +/- 5%) > or = MK801 (67 +/- 16%) > dextrorphan (47 +/- 16%) > dextromethorphan (31 +/- 12%) > ketamine (17 +/- 15%). In the nerve injury model, no supraspinal action was seen after intracerebroventricular injections of dextromethorphan and ketamine. NMDA antagonists by the spinal route appear to be useful therapeutic agents for chemically induced facilitated pain as well as nerve injury induced tactile allodynia. It is not known what accounts for the wide range of efficacies.

2-Amino-5-phosphonovalerate↗
PubMed1989

Aspartate neurotoxicity on cultured cortical neurons.

L-aspartate neurotoxicity was quantitatively characterized in murine cortical cell cultures. Five-minute exposure to 30 microM-3 mM L-aspartate resulted in concentration-dependent (ED50 about 190 microM) neuronal destruction over the next 10 hr; glia were not injured. D-aspartate and L-aspartate were roughly equipotent neurotoxins. Ion substitution experiments suggested that L-aspartate neurotoxicity is comprised of both acute, sodium-dependent "excitotoxicity" and delayed, calcium-dependent degeneration, with the latter predominant under conditions of brief exposure. Aspartate neurotoxicity could be attenuated by D-2-amino-5-phosphonovalerate (D-APV), dextrorphan, ketamine, and kynurenate, but not by L-glutamate diethyl ester or gamma-D-glutamylaminomethyl sulfonate, consistent with principal involvement of N-methyl-D-aspartate receptors. D-APV and dextrorphan produced different effects on the aspartate concentration-toxicity relation; the former drug was consistent with a competitive and the latter with a noncompetitive mechanism of antagonism.

Animals↗